Menin-Mixed Lineage Leukemia protein-protein interaction interface (Menin-MLL)

Menin is a scaffold protein encoded by the MEN1 gene that plays a dual role in human cancer, acting as a tumor suppressor in endocrine tissues and an oncogenic cofactor in certain leukemias [1.1.1, 1.4.1]. The Menin-Mixed Lineage Leukemia (MLL) protein-protein interaction interface is a critical site where Menin binds to the N-terminus of MLL1 (KMT2A) or its oncogenic fusion proteins [1.2.2, 1.3.1]. This interaction is essential for the recruitment of MLL complexes to target gene promoters, such as HOXA9 and MEIS1, which are key drivers of leukemogenesis in MLL-rearranged and NPM1-mutated leukemias [1.1.2, 1.4.3]. By disrupting this interface with small-molecule inhibitors, the expression of these pro-leukemic genes is suppressed, leading to the induction of myeloid differentiation and growth arrest in cancer cells [1.3.2, 1.3.5]. Clinical-stage inhibitors like revumenib and ziftomenib have demonstrated promising therapeutic activity in patients with relapsed or refractory acute leukemias [1.2.3, 1.3.3]. However, clinical challenges include the management of differentiation syndrome and the potential for acquired resistance through mutations in the Menin binding pocket [1.3.3, 1.3.5].

Other names

MEN1-MLL interactionMenin-KMT2A interactionMenin-MLL1 interactionMenin-MLL fusion protein interaction

Small-molecule inhibitors bind to the central pocket of Menin, competitively inhibiting its interaction with the N-terminal MLL-binding motifs (MBM1 and MBM2) of MLL1 or MLL-fusion proteins [1.1.1, 1.3.1]. This disruption leads to the displacement of the MLL complex from the promoters of leukemogenic target genes like HOXA9 and MEIS1, resulting in transcriptional repression and induction of cell differentiation [1.1.2, 1.3.2].